Carfilzomib, (2S)—N-{(1S)-1-Benzyl-2-[((1S)-3-methyl-1-{[(2R)-2-methyloxiran-2-yl]carbonyl}butyl)amino]-2-oxoethyl}-4-methyl-2-({(2S)-2-[(morpholin-4-ylacetyl)amino]-4-phenylbutanoyl}amino)pentanamide, is represented by the Formula

Carfilzomib (CFZ, marketed under the tradename Kyprolis, Onyx Pharmaceuticals, Inc.) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. It is an analog of epoxomicin.
The U.S. Food and Drug Administration (FDA) approved it on 20 Jul. 2012 for use in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma, who have received one to three prior lines of therapy. It is also indicated for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy. Carfilzomib as represented by Formula I is first disclosed in WO 05105827/U.S. Pat. No. 7,417,042.
U.S. Pat. Nos. 7,417,042; 7,232,818 and 8,207,297 describe a process for the preparation of Carfilzomib. The Scheme is summarized below in scheme 1:
wherein, “Boc” means tert-butoxycarbonyl; Bz and Bn means benzoyl and benzyl groups respectively; MeCN means acetonitrile; TFA means trifluoroacetic acid; DMF means dimethyl formamide; DCM means Dichloromethane; DIEA means diisopropyl ethyl amine; HOBT means hydroxyl benzatriazole; PyBop means benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate. The Carfilzomib thus obtained therein was crystallized in presence of methanol and water, and isolated by filtration.
Yet another process is described in Nature of Pharmacophore; Micheal Screen, et al. J. Biol. Chem. 2010, 285:40125-40134. The Scheme is summarized below in Scheme 2.
wherein, “HBTU” means N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate. The Carfilzomib thus obtained therein was purified by column chromatography.
U.S. Pat. No. 8,367,617 discloses a crystalline form of Carfilzomib, salts of Carfilzomib, wherein the salt counterion is selected from citrate, tartrate, trifluoroacetate, methanesulfonate, toluenesulfonate, chloride, and bromide.
Unfortunately, an acetamide impurity of Formula II,
is inevitably formed in prior art processes described in U.S. Pat. Nos. 7,417,042; 7,232,818 and 8,207,297 and this impurity is difficult to separate from the desired end product. Even by using different purification methods including recrystallization, the impurity remains in an undesired amount.
Thus, there still remains the need to formulate efficient and economical purification procedure especially, for use on an industrial scale.
The inventors have now discovered a process for purification of Carfilzomib by reducing the amount of the acetamide impurity of formula II, hereinafter referred as acetamide impurity without using potential time consuming crystallization and recrystallization techniques or expensive chromatography. Rather the inventors have found that the best way to remove this impurity is by formation of suitable salt of Carfilzomib with weak acid. Surprisingly it is found, that the use of oxalate salt of Carfilzomib as an intermediate within the process of the present invention leads to superior results. Finally this oxalate salt of Carfilzomib is converted to Carfilzomib by reacting it with a base, wherein the Carfilzomib thus obtained has less than 0.10 wt % of acetamide impurity.